Hepatocyte growth factor (HGF) was first purified from human and rabbit plasma and rat platelets on the basis of its ability to stimulate mitogenesis of rat hepatocytes (E. Gohoda et al., J. Clin. Invest. 81, 414 (1988); R. Zarnegar and G. Michalopoulos, Cancer Res. 49, 3314 (1989); T. Nakamura et al. FEBS Lett. 224, 311 (1987)). Thus, HGF may act as a humoral factor promoting liver regeneration after partial hepatectomy or liver injury (G. K. Michalopoulos, FASEB J. 4, 176 (1990)). The same factor was purified from human fibroblast culture medium and shown to act on melanocytes and a variety of epithelial and endothelial cells (J. S. Rubin et al., Proc. Natl. Acad. Sci. U.S.A. 88, 415 (1990)). Together with evidence of HGF expression in several organs (J. S. Rubin et al., Proc. Natl. Acad. Sci. U.S.A. 88, 415 (1990); K. Tashiro et al. Proc. Natl. Acad. Sci. U.S.A. 87, 3200 (1990); R. Zarnegar et al., Proc. Natl. Acad. Sci. U.S.A. 87, 1252 (1990); T. Kinoshita et al. Biochem. Biophys. Res. Comm. 165, 1229 (1989)), these findings indicate that HGF may also act as a paracrine mediator of proliferation for a broad spectrum of cell types. Molecular cloning of HGF revealed a remarkable structural homology to plasminogen and related serine proteases (J. S. Rubin et al., Proc. Natl. Acad. Sci. U.S.A. 88, 415 (1990); T. Nakamura et al., Nature 342, 440 (1989); K. Miyazawa et al., Biophys. Res. Comm. 163, 967 (1989)). Recent evidence that HGF induces rapid tyrosine phosphorylation of proteins in intact target cells suggests that a tyrosine kinase receptor might mediate its mitogenic signal (J. S. Rubin et al., Proc. Natl. Acad. Sci. U.S.A. 88,415 (1990)).
HGF is structurally related to the family of serine proteases that includes plasminogen, prothrombin, urokinase, and tissue plasminogen activator (J. S. Rubin et al., Proc. Natl. Acad. Sci. U.S.A. 88, 415 (1990)); T. Nakamura et al., Nature 342, 440 (1989)). As defined in the present invention, HGF includes a variant of HGF previously characterized as a broad-spectrum mitogen called plasminogen like growth factor (PLGF). Several proteases, including members of the serine protease family, stimulate DNA synthesis presumably through a proteolytic mechanism similar to tryptic activation of the insulin receptor (S. E. Shoelson et al. J. Biol. Chem. 263, 4852 (1988)). Only urokinase has been found to associate with a specific cell-surface receptor, which itself bears no homology to any known tyrosine kinase receptors (A. L. Roldan et al., EMBO J. 9, 467 (1990)).
It is clear that a need exists to identify the receptor of HGF. The present invention describes the complex comprising HGF and met proto-oncogene protein and identifies the met proto-oncogene as the receptor for HGF. The met proto-oncogene protein is a member of the tyrosine kinase growth factor receptor family. Knowledge of this receptor/ligand relationship should facilitate the study of proliferative disorders in which expression of these molecules may play an important role. Additionally, identification of the met proto-oncogene receptor HGF complex provides a means for identifying tissues other than liver tissue affected by factor binding.